April 28, 2016
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Tafinlar

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Tafinlar

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in another section of the label:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to TAFINLAR as a single agent and in combination with trametinib.

TAFINLAR Administered As A Single Agent

The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies]. Trial 1, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m² intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology ( ≥ Grade 2), corrected QT interval greater than or equal to 480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% White, and had a median age of 53 years.

The most commonly occurring adverse reactions ( ≥ 20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent ( ≥ 2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%). 13

Table 3: Select Common Adverse Reactions Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4) of Patients Treated with TAFINLARa

Primary System Organ Class
Preferred Term
TAFINLAR
N = 187
Dacarbazine
N = 59
All Grades (%) Grades 3 and 4b (%) All Grades (%) Grades 3 and 4 (%)
Skin and subcutaneous tissue disorders
Hyperkeratosis 37 1 0 0
Alopecia 22 NAf 2 NAf
Palmar-plantar erythrodysesthesia syndrome 20 2 2 0
Rash 17 0 0 0
Nervous system disorders
Headache 32 0 8 0
General disorders and administration site conditions
Pyrexia 28 3 10 0
Musculoskeletal and connective tissue disorders
Arthralgia 27 1 2 0
Back pain 12 3 7 0
Myalgia 11 0 0 0
Neoplasms benign, malignant, and unspecified (including cysts and polyps)
Papillomac 27 0 2 0
cuSCCd,e 7 4 0 0
Respiratory, thoracic, and mediastinal disorders
Cough 12 0 5 0
Gastrointestinal disorders
Constipation 11 2 14 0
Infections and infestations
Nasopharyngitis 10 0 3 0
a Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity.
b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1).
c Includes skin papilloma and papilloma.
d cuSCC = cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma.
e Cases of cuSCC were required to be reported as Grade 3 per protocol.
f NA = not applicable.

Table 4: Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in Trial 1 [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)]a

Test TAFINLAR
N = 187
DTIC
N = 59
All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%)
Hyperglycemia 50 6 43 0
Hypophosphatemia 37 6b 14 2
Increased alkaline phosphatase 19 0 14 2
Hyponatremia 8 2 3 0
a Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity.
b Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1).

Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with TAFINLAR were:

Gastrointestinal Disorders: Pancreatitis.

Immune System Disorders: Hypersensitivity manifesting as bullous rash.

Renal and Urinary Disorders: Interstitial nephritis.

TAFINLAR Administered With Trametinib

The safety of TAFINLAR when administered with trametinib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma who received TAFINLAR in two trials, Trial 2 (n = 209) a multicenter, double-blind, randomized (1:1), active controlled trial and Trial 3 (n = 350) a multicenter, open-label, randomized (1:1), active controlled trial. In Trials 2 and 3, patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or a known history of G6PD deficiency [see Clinical Studies].

Among these 559 patients, 199 (36%) were exposed to TAFINLAR for > 6 months to 12 months while 185 (33%) were exposed to TAFINLAR for ≥ 1 year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline and 0.5% had a history of brain metastases.

The most commonly occurring adverse reactions ( ≥ 20%) for TAFINLAR in patients receiving TAFINLAR plus trametinib in Trials 2 and 3 were: pyrexia, rash, chills, headache, arthralgia, and cough.

Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, observed in Trial 2.

The demographics and baseline tumor characteristics of patients enrolled in Trial 2 are summarized in Clinical Studies [see Clinical Studies]. Patients receiving TAFINLAR plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to TAFINLAR. Among the 209 patients receiving TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for > 6 months to 12 months while 46% were exposed to TAFINLAR for > 1 year.

In Trial 2, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients receiving TAFINLAR plus trametinib; the most common was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of Tafinlar occurred in 56% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%).

Table 5: Select Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in Trial 2a

Adverse Reactions Pooled TAFINLAR plus Trametinib
N = 559
Trial 2
TAFINLAR plus Trametinib
N =209
TAFINLAR
N = 211
All Grades (%) Grades 3 and 4b (%) All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%)
General disorders and administrative site conditions
  Pyrexia 54 5 57 7 33 1.9
  Chills 31 0.5 31 0 17 0.5
Gastrointestinal disorders
  Constipation 13 0.2 13 0.5 10 0
Nervous system disorders
  Headache 30 0.9 33 0.5 30 1.4
  Dizziness 11 0.2 14 0 7 0
Musculoskeletal, connective tissue, and bone disorders
  Arthralgia 25 0.9 26 0.9 31 0
  Myalgia 15 0.2 13 0.5 13 0
Skin and subcutaneous tissue disorders
  Rashc 32 1.1 42 0 27 1.4
  Dry skin 10 0 12 0 16 0
Respiratory, thoracic, and mediastinal disorders
  Cough 20 0 21 0 21 0
Infections and infestations
  Nasopharyngitis 12 0 12 0 10 0
a NCI CTCAE version 4
b Grade 4 adverse reactions limited to headache (n = 1).
c Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis.

Other clinically important adverse reactions for TAFINLAR across Trials 2 and 3 (N = 559) observed in less than 10% of patients receiving TAFINLAR in combination with trametinib were:

Gastrointestinal Disorders: pancreatitis

Subcutaneous Tissue Disorders: panniculitis

Table 6: Select Treatment-Emergent Laboratory Abnormalities Occurring at ≥ 10% (All Grades) of Patients Receiving TAFINLAR with Trametinib in Trial 2

Test Pooled TAFINLAR plus Trametinib
N = 559a
Trial 2
TAFINLAR plus Trametinib
N = 209b
TAFINLAR
N = 211b
All Grades (%) Grades 3 and 4c (%) All Grades (%) Grades 3 and 4c (%) All Grades (%) Grades 3 and 4c (%)
Liver Function Tests
  Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5
Chemistry
  Hyperglycemia 60 4.7 65 6 57 4.3
  Hypophosphatemia 38 6 38 3.8 35 7
  Hyponatremia 25 8 24 6 14 2.9
a For these laboratory tests the denominator is 556.
b For these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm.
c Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the Trial 2 combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm.

Read the Tafinlar (dabrafenib capsules) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Effects Of Other Drugs On Dabrafenib

Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see CLINICAL PHARMACOLOGY]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Effects Of Dabrafenib On Other Drugs

Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see CLINICAL PHARMACOLOGY]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/22/2016

Side Effects
Interactions

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